Effective combinatorial immunotherapy for castration-resistant prostate cancer

Abstract

A significant fraction of advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC)1. Immune checkpoint blockade (ICB) using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types2. However, mCRPC showed overwhelming de novo resistance to ICB3–5, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumor immune evasion6. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients7–9. Mouse models of PCa show that MDSCs (CD11b+ Gr1+) promote tumor initiation10 and progression11. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here we developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC.

The combination of checkpoint immunotherapy and targeted therapy in cancer

“…Robust synergistic responses were obtained in a prostate cancer mouse model with the combination of ICB and the multikinase inhibitor cabozantinib or the phosphoinositide 3-kinase (PI3K)/ mTOR dual inhibitor BEZ235 (56). Both cabozantinib and BEZ235 diminish MDSCs and enhance ICB through inhibition of PI3K signaling and downregulation of cytokines responsible for immunosuppression-related gene expression (56). In renal cell carcinoma (RCC), antiangiogenic agents are evaluated in combination with ICB.…”

Local Immune Responsiveness of Mice Bearing Premalignant Oral Lesions to PD-1 Antibody Treatment

“…Thus, it may be that the transient nature of the increase in cytokines due to PD-1 antibody treatment could be due to development of immune inhibitory mechanisms other than through the PD-1 immune checkpoint axis. This concept is supported by other studies showing only modest clinical effectiveness of checkpoint blockade treatment in a prostate cancer model, but a robust synergistic response when checkpoint blockade treatment was combined with kinase-inhibitory treatment targeting infiltration by myeloid-derived suppressor cells [33]. A separate study also demonstrated alternative inhibitory mechanisms, such as IL-17 stimulation of intratumoral neutrophil infiltration, as contributors to PD-1 blockade resistance by lung cancer [34].…”

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

“…In recent years, cancer immunotherapy has drawn much attention due to its remarkable curative effects . Immune cells, including T cells, NK cells, and DCs play a key role in antitumor immune responses and cancer immunotherapy.…”